LaPlante Kerry L, Rybak Michael J, Tsuji Brian, Lodise Thomas P, Kaatz Glenn W
Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Department of Pharmacy Practice, School of Medicine, Wayne State University, 259 Mack Ave., Detroit, MI 48201, USA.
Antimicrob Agents Chemother. 2007 Apr;51(4):1315-20. doi: 10.1128/AAC.00646-06. Epub 2007 Feb 12.
The potential for resistance development in Streptococcus pneumoniae secondary to exposure to gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin at various levels was examined at high inoculum (10(8.5) to 10(9) log10 CFU/ml) over 96 h in an in vitro pharmacodynamic (PD) model using two fluoroquinolone-susceptible isolates. The pharmacokinetics of each drug was simulated to provide a range of free areas under the concentration-time curves (fAUC) that correlated with various fluoroquinolone doses. Potential first (parC and parE)- and second-step (gyrA and gyrB) mutations in isolates with raised MICs were identified by sequence analysis. PD models simulating fAUC/MICs of 51 and<or=60, 34 and 37, <or=82 and<or=86, and<or=24 for gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin, respectively, against each isolate were associated with first-step parC (S52G, S79Y, and N91D) and second-step gyrA (S81Y and S114G) mutations. For each fluoroquinolone a delay of first- and second-step mutations was observed with increasingly higher fAUC/MIC ratios and recovery of topoisomerase mutations in S. pneumoniae was related to the fAUC/MIC exposure. Clinical doses of gatifloxacin, gemifloxacin, and moxifloxacin exceeded the fAUC/MIC resistance breakpoint against wild-type S. pneumoniae, whereas those of levofloxacin (500 and 750 mg) were associated with first- and second-step mutations. The exposure breakpoints for levofloxacin were significantly different (P<0.001) from those of the newer fluoroquinolones gatifloxacin, gemifloxacin, and moxifloxacin. Additionally, moxifloxacin breakpoints were significantly lower (P<0.002) than those of gatifloxacin. The order of resistance development determined from fAUC/MIC breakpoints was levofloxacin>gatifloxacin>moxifloxacin=gemifloxacin, which may be related to structural differences within the class.
在体外药效学（PD）模型中，使用两株对氟喹诺酮敏感的肺炎链球菌分离株，在高接种量（10⁸.⁵至10⁹ log₁₀ CFU/ml）下，于96小时内检测了不同水平的加替沙星、吉米沙星、左氧氟沙星和莫西沙星导致肺炎链球菌产生耐药性的可能性。模拟了每种药物的药代动力学，以提供一系列与不同氟喹诺酮剂量相关的浓度-时间曲线下的游离面积（fAUC）。通过序列分析鉴定了MIC升高的分离株中潜在的第一步（parC和parE）和第二步（gyrA和gyrB）突变。针对每种分离株，模拟加替沙星、吉米沙星、左氧氟沙星和莫西沙星的fAUC/MIC分别为51和/或60、34和37、≤82和≤86以及≤24的PD模型与第一步parC（S52G、S79Y和N91D）和第二步gyrA（S81Y和S114G）突变相关。对于每种氟喹诺酮，随着fAUC/MIC比值升高，观察到第一步和第二步突变出现延迟，并且肺炎链球菌中拓扑异构酶突变的恢复与fAUC/MIC暴露有关。加替沙星、吉米沙星和莫西沙星的临床剂量超过了针对野生型肺炎链球菌的fAUC/MIC耐药断点，而左氧氟沙星（500和750 mg）的临床剂量与第一步和第二步突变相关。左氧氟沙星的暴露断点与新型氟喹诺酮加替沙星、吉米沙星和莫西沙星的暴露断点有显著差异（P<0.001）。此外，莫西沙星的断点显著低于加替沙星（P<0.002）。根据fAUC/MIC断点确定的耐药性发展顺序为左氧氟沙星>加替沙星>莫西沙星=吉米沙星，这可能与该类药物的结构差异有关。
